Consumption of oxygen: a mitochondrial-generated progression signal of advanced cancer
Consumption of oxygen: a mitochondrial-generated progression signal of advanced cancer
复制标题
DOI：
10.1038/cddis.2011.141
复制
发表时间：
2012-01-01
影响因子：
9
通讯作者：
Higuchi, M.
中科院分区：
文献类型：
--
作者：
Cook, C. C.;Kim, A.;Higuchi, M.
线粒体基因组的突变、缺失和耗竭等变化在癌症中很常见，可以决定癌症的晚期表型；然而，详细的机制尚未阐明。我们观察到线粒体基因组的缺失可逆地诱导了原致癌Ras的过度表达和激活，特别是K-Ras 4A，它负责AKT和ERK的激活，导致前列腺癌和乳腺癌的晚期表型。Ras的激活是由甲基戊二酸途径的限速酶——3-羟基-3-甲基-戊二酸辅酶a还原酶（HMGR）的过度表达引起的。已知缺氧可诱导HMGR的蛋白酶体降解。高线粒体DNA含量的分化良好的前列腺癌和乳腺癌细胞消耗大量氧气并诱导缺氧。线粒体基因组的缺失减少了细胞的耗氧量，增加了细胞内的氧浓度。低氧到正氧的转变通过抑制蛋白酶体降解导致HMGR的过度表达。因此，线粒体基因组含量的减少通过缺氧向正氧转移诱导HMGR过表达，随后内源性诱导甲羟戊酸途径激活Ras介导晚期表型。在体外细胞系模型和体内组织标本中，线粒体基因组含量的降低与前列腺癌的侵袭性表型相关。我们的结果阐明了一个连贯的机制，直接将线粒体基因组与疾病的晚期进展联系起来。细胞死亡与疾病（2012）3,e258；doi: 10.1038 / cddis.2011.141;2012年1月19日在线发布
Changes in mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced phenotype of cancer; however, detailed mechanisms have not been elucidated. We observed that loss of mitochondrial genome reversibly induced overexpression and activation of proto-oncogenic Ras, especially K-Ras 4A, responsible for the activation of AKT and ERK leading to advanced phenotype of prostate and breast cancer. Ras activation was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to induce proteasomal degradation of HMGR. Well differentiated prostate and breast cancer cells with high mitochondrial DNA content consumed a large amount of oxygen and induced hypoxia. Loss of mitochondrial genome reduced oxygen consumption and increased in oxygen concentration in the cells. The hypoxic-to-normoxic shift led to the overexpression of HMGR through inhibiting proteasomal degradation. Therefore, reduction of mitochondrial genome content induced overexpression of HMGR through hypoxic to normoxic shift and subsequently the endogenous induction of the mevalonate pathway activated Ras that mediates advanced phenotype. Reduction of mitochondrial genome content was associated with the aggressive phenotype of prostate cancer in vitro cell line model and tissue specimens in vivo. Our results elucidate a coherent mechanism that directly links the mitochondrial genome with the advanced progression of the disease. Cell Death and Disease (2012) 3, e258; doi:10.1038/cddis.2011.141; published online 19 January 2012